HIV: GENDER AND SEX HORMONE EFFECTS ON T CELL KINETICS

描述：（申请人提供摘要）性别差异已被 记录了免疫功能的许多方面，并可能由 主要生殖激素（雄激素、雌激素和孕酮）。性别 人类免疫缺陷病毒1型自然史的差异 （HIV-I）感染也有描述。特别是， HIV-1病毒载量（VL）与疾病进展之间的关系一直是 与男性相比，女性的报告。性别或 生殖激素对T细胞增殖和存活的影响，包括 胸腺产生T细胞，在HIV- 1感染的情况下， 直接测试。我们建议进行的研究，目的是 将男性和女性T细胞周转的自然史与早期T细胞周转的自然史进行比较， HIV-1疾病，并确定性类固醇对T细胞的影响 周转，包括胸腺生成，在HIV-1感染。这些研究目前 由于最近开发了稳定的同位素质量， 用于直接测量纯化T的动力学的光谱技术 细胞亚群。将进行三项临床研究。研究 #1将比较CD 4+和CD 8 + T细胞动力学的自然史， 未治疗的、CD 4匹配的早期HIV-1感染的男性和女性（CD 4计数 500-750个细胞/uL;每组n~ 15）。T细胞动力学将通过两个 互补技术（[6，6 - 2 H2]葡萄糖掺入和消失曲线， 表征记忆/效应-表型T细胞动力学;长期2 H2O 掺入，以表征初始表型T细胞的动力学）。 基线，然后在3-4年随访期间每12-18个月一次。相关性 VL、CD 4计数、胸腺质量（通过CT扫描）、切除环和血液之间的关系 将在男性和女性中比较测量（细胞因子、激素）。我们 假设是T细胞动力学中机会将与CD 4计数一起跟踪， 两种性别，但女性的VL较低。研究#2将比较 HIV-1感染的青春期前男孩和女孩的青春期（每组n=8）。的 门诊2 H2O方法将用于测量T细胞动力学。其他 参数将与研究#1中的参数相关。核心假设是， 性类固醇的增加会抑制男女的胸腺生成。也许 更能影响男生。研究#3将比较生殖 男性和女性HIV-1感染者性腺功能减退激素替代治疗 感染（每组n=8）。用于测量T细胞动力学的2 H2O方法将 被利用与研究I和2中的其他测量结果相同。前提是 性类固醇将减少男性和女性中幼稚表型T细胞的产生， 女性，可能对男性的影响更大。总之，我们建议 在体内直接确定性类固醇是否改变T细胞动力学 （特别是胸腺生成）。以及T细胞 与男性相比，女性中CD 4计数比VL更好地跟踪周转。

Description: (Abstract Provided by Applicant) Gender differences have been documented for many aspects of immune function and are likely mediated by the major reproductive hormones (androgens, estrogens and progesterone). Gender differences in the natural history of human immunodeficiency virus-type 1 (HIV-l) infection have also been described. In particular, a different relationship between HIV-1 viral load (VL) and progression of disease has been reported for women as compared to men. The in vivo effects of gender or reproductive hormones on proliferation and survival of T cells, including thymic production of T cells, in the setting of HIV- 1 infection have not been directly tested, however. The objectives of our proposed studies are to compare the natural history of T cell turnover in men and women with early HIV-1 disease and to establish the consequences of sex steroids on T cell turnover, including thymopoiesis, in HIV-l infection. These studies are now possible in humans because of the recent development of stable isotope-mass spectrometric techniques for directly measuring the kinetics of purified T cell subpopulations in vivo. Three clinical studies will be performed. Study #1 will compare the natural history of CD4+ and CD8+ T cell kinetics in untreated, CD4-matched men and women with early HIV-l infection (CD4 counts 500-750 cells/uL; n~l5 per group). T cell kinetics will be measured by two complementary techniques ([6,6-2H2] glucose incorporation and die-away curves, to characterize memory/effector-phenotype T cell dynamics; long term 2H2O incorporation, to characterize kinetics of naive-phenotype T cells) at baseline then every 12-18 months over a 3-4 year follow-up. Correlation between VL, CD4 count, thymic mass (by CT scan), excision circles, and blood measurements (cytokines, hormones) will be compared in men and women. Our hypothesis is that chances in T cell kinetics will track with CD4 count in both genders, but at a lower VL in women. Study #2 will compare the effects of puberty in HIV-1 infected pre-adolescent boys and girls (n=8 per group). The outpatient 2H2O approach will be used to measure T cell dynamics. Other parameters will be correlated as in study #1. The central hypothesis is that the rise in sex steroids will suppress thymopoiesis in both genders. perhaps greater affecting boys. Study #3 will compare the effects of reproductive hormone replacement therapy in hypogonadal adult men and women with HIV-1 infection (n=8 per group). The 2H2O method for measuring T cell dynamics will be used. with other measurements as in Studies I and 2. The hypothesis is that sex steroids will reduce production of naive-phenotype T cells in both men and women, with perhaps a greater effect in men. In summary, we propose to determine directly, in vivo, whether sex steroids alter T cell kinetics (particularly thymopoiesis) in HIV-1 infected humans. and whether T cell turnover tracks better with CD4 count than VL in women, compared to men.